Cellular and Molecular Biology


Suicide gene therapy with Herpes simplex virus thymidine kinase and ganciclovir is enhanced with connexins to improve gap junctions and bystander effects

T.W. Nicholas1, S.B. Read1, F.J. Burrows3,4 and C.A. Kruse1,2,3

1Department of Immunology, 2Department of Pathology, University of Colorado Health Sciences Center, Denver, Colorado and 3Chiron Technologies Center for Gene Therapy, San Diego, California, USA
4Present address: Conforma Therapeutics, San Diego, CA, USA

Offprint requests to: Carol A. Kruse, Ph.D., University of Colorado Health Sciences Center, Room 2653 School of Medicine, Campus Box B216, 4200 East 9th Avenue, Denver, Colorado 80262, USA. Fax: 303-315-6795. e-mail: carol.kruse@uchsc.edu


Summary. Connexins are proteins that form gap junctions between cells in various mammalian tissues. Because of their role in intercellular communication, connexins are important in the bystander cell death seen in Herpes simplex virus-thymidine kinase (HSV-TK) gene therapy for brain tumors. A selective review of connexin transduction/transfection studies with particular emphasis to central nervous system tumor cells is presented. In addition, specific references to studies with cell types that demonstrate low gap junction intercellular communication are presented. Data are included with the HT-29 colorectal tumor cell line to support the concept that enhancing gap junction protein expression in otherwise low gap junction communicating HT-29 cells increases bystander cell death and reduces tumor burden beyond what might be expected from HSV-TK and ganciclovir (GCV) treatment alone. Maximum in vitro bystander cell death was always produced when GCV treated co-cultures of TK-transduced and non-TK-transduced HT-29 cell lines were also transduced with connexin-43. When connexin was present in only one group of cells in the co-culture, there was more bystander cell death observed with connexin transduced into the non- TK-transduced cells, rather than the TK-transduced cells. The data presented reinforces conclusions made from earlier findings from cell line mixing experiments in which the non- TK-transduced cell population determined the level of bystander cell death (Burrows et al., 2002). Histol. Histopathol. 18, 495-507 (2003)

Key words: Glioma, Connexin, Gap junctions, Suicide gene therapy, Bystander effect

DOI: 10.14670/HH-18.495